Glyco-metal-organic frameworks-based hepatic targeted therapeutic drug and preparation method thereof

Abstract

The disclosure discloses a glyco-metal-organic frameworks-based hepatic targeted therapeutic drug and a preparation method thereof, and belongs to the field of biomedicine. The disclosure loads a chemotherapeutic drug onto specific metal-organic frameworks, and modifies targeted molecule galactose on the surface of the materials through amide reaction. The biocompatibility and cytotoxicity of the obtained hepatic targeted therapeutic drug have been carefully evaluated at the cellular level. The hepatic targeted therapeutic drug of the disclosure has good stability and acidic pH triggered drug release property, and can exert the synergistic therapeutic effect of photodynamic therapy and chemotherapy. In addition, in vivo behavioral tracing and therapeutic efficacy are evaluated in mouse models with subcutaneous solid tumor and tumor in situ, and the disclosure is expected to play a huge role in clinical applications.

What is claimed is: 
     
       1. A method for preparing a drug for targeted treatment of liver diseases, wherein the drug has a structure having components A, B, C and D;
 wherein A is selected from one or more of the same or different chemotherapeutic drugs: doxorubicin, sorafenib and 5-fluorouracil; 
 B is metal-organic frameworks (MOFs) with a photosensitizer as a linking arm; 
 C is a linking group, and the linking group is-CO-PEG-CO-; 
 D is galactose or a monosaccharide or oligosaccharide molecule containing a galactosamine residue; 
 wherein the MOFs are used as a carrier to load the chemotherapeutic drugs, and a surface of the MOFs is linked to the galactose or the monosaccharide or oligosaccharide containing the galactosamine residue through the -OCO-PEG-COO linking group; 
 wherein the MOFs are selected from PCN-224 and PCN-222; 
 wherein the method comprises the following steps: 
 (1) preparing chemotherapeutic drug@-PCN-224: 
 dispersing ZrOCl 2 ·8H 2 O, TCPP and benzoic acid in an organic solvent; mixing the materials uniformly; adding a chemotherapeutic drug to form a mixed system; performing a reaction at 80-100° C.; then performing solid-liquid separation to collect precipitate; washing and drying the precipitate to obtain chemotherapeutic drug@PCN-224; wherein the chemotherapeutic drug is selected from one or more of the following: doxorubicin, sorafenib, and 5-fluorouracil; 
 (2) dispersing the chemotherapeutic drug@PCN-224 obtained in step (1) and COOH-PEG-COOH in water to form a mixed solution; performing a reaction at room temperature; after the reaction, performing solid-liquid separation to collect precipitate; washing and drying the precipitate to obtain carboxyl-modified chemotherapeutic drug@PCN-224; and 
 (3) dissolving the carboxyl-modified chemotherapeutic drug@PCN-224 obtained in step (2), amino-modified galactose, and a condensing agent in water; performing a reaction at room temperature; after the reaction, performing solid-liquid separation to collect precipitate; washing and drying the precipitate to obtain chemotherapeutic drug@Gal-PCN-224. 
 
     
     
       2. The method of  claim 1 , wherein a mass ratio of the chemotherapeutic drug to the ZrOCl 2 ·8H 2 O to the TCPP to the benzoic acid in the step (1) is 1:(5-8):(2-4):(50-60). 
     
     
       3. The method of  claim 1 , wherein a concentration of the chemotherapeutic drug in the mixed system in the step (1) is 0.4-0.6 mg/mL. 
     
     
       4. The method of  claim 1 , wherein a mass ratio of the chemotherapeutic drug@PCN-224 to the COOH-PEG-COOH in the step (2) is (2-2.5):1. 
     
     
       5. The method of  claim 1 , wherein a mass concentration of the chemotherapeutic drug@PCN-224 in the mixed solution in the step (2) is 0.8-1.2 mg/mL. 
     
     
       6. The method of  claim 1 , wherein in step (3), a mass ratio of the carboxyl-modified chemotherapeutic drug@PCN-224 to the amino-modified galactose is 1:(0.5-0.8). 
     
     
       7. The method of  claim 1 , wherein the condensing agent in step (3) contains 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide. 
     
     
       8. The method of  claim 7 , wherein a mass ratio of the 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to the N-hydroxysuccinimide in the condensing agent is 1.7:1.